Mortality rates in Appalachia have progressively increased over recent years, in contrast to decreasing mortality rates observed in the remainder of the US. West Virginia was ranked 47th overall among the 50 states in the 2015 America's Health Rankings. In addition, WV remains at, or near, the bottom for a number of chronic diseases including cancer and cardiovascular disease. These observations alone do not capture the entire continuum of health related challenges in the state or region, but clearly emphasize the need for continued focus on, and investment in, research that underpins real solutions. The West Virginia Clinical and Translational Science Institute (WVCTSI) was created in 2012 through the initial Clinical and Translational Research (CTR) award and has subsequently formed a well-connected, statewide research network, creating the infrastructure to address the substantial health disparities that exist in West Virginia. The overarching goal of the WVCTSI is to serve as a collaborative hub to lead statewide innovation in clinical and translational research, catalyzing and accelerating development of solutions to vexing health problems. Over the past four years, WVCTSI has been a transformative force, implementing investigator mentoring services, establishing pilot project funding, forming a practice-based research network of 68 sites (mostly rural), creating an integrated data repository of two million unique electronic medical records, developing a broad-based culture of research integrity, and working with our partners to establish trust and effective collaboration. WVCTSI is now well positioned to attain the goals of this renewal application that include: 1) building sustainable research infrastructure that substantively contributes to improving WV health outcomes by 2022, 2) recruiting the next generation of clinician scientists and translational researchers that excel in team science and are positioned for long-term success, and 3) actively engaging with multiple stakeholders that include communities, medical providers, and policy makers to drive research that improves health of West Virginians. Our partners include all academic medical centers within the state as well as the University of Kentucky, the Veterans Administration, and the National Institute for Occupational Safety and Health. Through its collective activities and powerful partnerships, the WVCTSI will play a critical role in reversing the trend of increasing mortality rates in West Virginia and serve as a model for developing effective research infrastructure that provides solutions to regional health issues.